tbuckley/cabot-search huggingface dataset:
Abstract 3328: Using Luminex approach to develop a panel of anti-TAA autoantibodies for the detection of prostate cancer
Authors: Cuipeng Qiu, Xiao Wang, Serina Batson, Giulio Francia, Jian-Ying Zhang
Journal: Cancer Research (2023)

Abstract Autoantibodies to tumor-associated antigens (TAAs) have been demonstrated as reporters in early carcinogenesis. Luminex technology enables the development of simultaneous detection of multiple autoantibodies. This study aimed to use Luminex technology to evaluate and develop an optimal panel for the detection of prostate cancer (PCa) based on autoantibodies to fourteen TAAs (p53, p16, IMP2, IMP3, SOX2, BIRC5, HIF1-α, HSP60, ENO1, CTAG1B, MUC1, Her2, GAL1, and GAL3) associated with cancers. A total of 163 samples including 91 PCa sera and 72 normal control sera were screened to evaluate the expression of fourteen autoantibodies by multiple autoantibody bead panel. Except for autoantibodies to Her2 and IMP3, twelve autoantibodies showed significantly high frequencies ranging from 19.8% to 51.6% in the PCa group at 95.8% specificity for normal controls. The area under the curve (AUC) of these twelve autoantibodies ranged from 0.609 to 0.868. After logistic regression modeling and leave-one-out cross-validation, an optimal panel with the combination of three autoantibodies to p16, IMP2, and HSP60 was developed, achieving an AUC of 0.909 with 71.4% sensitivity and 95.8% specificity. Autoantibody to HSP60 exhibiting the best performance with an AUC of 0.868 in the autoantibody bead panel was further validated by Enzyme-linked immunosorbent assay (ELISA) with a larger size sample containing 200 PCa sera and 137 normal control sera, it also showed an AUC of 0.848 to identify PCa from normal controls. Therefore, the autoantibody bead panel showed similar results to ELISA. In summary, we developed an optimal autoantibody bead-based panel for the detection of PCa. It could be used as a high throughput tool to facilitate Pca detection. Citation Format: Cuipeng Qiu, Xiao Wang, Serina Batson, Giulio Francia, Jian-Ying Zhang. Using Luminex approach to develop a panel of anti-TAA autoantibodies for the detection of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3328.
Abstract 625: PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven adaptive resistance
Authors: Chun Wai Wong, Christos Evangelou, Kieran N. Sefton, Rotem Leshem, Kleita Sergiou, Macarena Lucia Fernandez Carro, Erez Uzuner, Holly Mole, Brian A. Telfer, Daniel J. Wilcock, Michael P. Smith, Kaiko Kunii, Nicholas R. Perl, Paul Lorigan, Kaye J. Williams, Patricia E. Rao, Raghavendar T. Nagaraju, Mario Niepel, Adam F. Hurlstone
Journal: Cancer Research (2023)

Abstract Adaptive resistance limits immune checkpoint blockade therapy (ICBT) response duration and magnitude. Interferon γ (IFNγ), a critical cytokine that promotes cellular immunity, also induces adaptive resistance to ICBT. Using syngeneic mouse tumor models, we confirmed that chronic IFNγ exposure confers resistance to anti-Programmed cell death protein 1 (α-PD-1) therapy. We identified consistent upregulation of poly-ADP ribosyl polymerase 14 (PARP14) in both chronic IFNγ-treated cancer cells and patient melanoma with elevated IFNG expression. Knockdown or pharmacological inhibition of PARP14 increased effector T cell infiltration into tumors derived from cells pre-treated with IFNγ and decreased the presence of regulatory T cells, leading to restoration of α-PD-1 sensitivity. Finally, we determined that tumors which spontaneously relapsed following α-PD-1 therapy could be re-sensitized upon receiving PARP14 inhibitor treatment, establishing PARP14 as an actionable target to reverse IFNγ-driven ICBT resistance. Citation Format: Chun Wai Wong, Christos Evangelou, Kieran N. Sefton, Rotem Leshem, Kleita Sergiou, Macarena Lucia Fernandez Carro, Erez Uzuner, Holly Mole, Brian A. Telfer, Daniel J. Wilcock, Michael P. Smith, Kaiko Kunii, Nicholas R. Perl, Paul Lorigan, Kaye J. Williams, Patricia E. Rao, Raghavendar T. Nagaraju, Mario Niepel, Adam F. Hurlstone. PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven adaptive resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 625.
Abstract 1668: Targeting drug-induced tolerant &amp; resistant cell populations by novel ferroptosis inducer
Authors: Taronish Dubash, Maria Cristina Munteanu, Shrouq Farah, Cristian Nunez, Laurence Jadin, Branko Radetich, Darby Schmidt, Nadia Gurvich
Journal: Cancer Research (2023)

Abstract A subset of tumor cells escapes apoptotic and necroptotic death when subjected to chemo- or targeted therapy thereby entering a transient reversible less-proliferative “tolerant state.” Upon continuous drug treatment, these tumor cells become drug resistant, leading to metastases and cancer relapse. A long-standing goal in oncology has been to develop therapeutics to effectively target both cell states. Growing published evidence suggests that accumulation of reactive oxygen species and lipid remodeling make tolerant and resistant tumor cells more vulnerable to ferroptotic mode of cell death. To this end, we here characterize the activity of a proprietary inhibitor of GPX4, an enzyme that safeguards against ferroptosis, across a panel of tolerant and resistant cell line models. Drug tolerant and resistant cancer cell lines spanning three indications were generated by applying continuous treatments with relevant standard-of-cares (SOC) in vitro for short or long durations, respectively. Age-matched control cell lines were derived in parallel by treatment of parental cells with DMSO. Cells were subjected to high dose of SOC for nine days to generate tolerant lines, or to increased therapeutic doses of SOC over three months to generate resistant lines, after which resistance to SOCs was confirmed. In accordance with our hypothesis, we found that drug tolerant lines demonstrated enhanced sensitivity to GPX4 inhibition compared to age-matched control lines. Furthermore, we noted that resistant tumor cell lines retained exquisite sensitivity to GPX4 inhibition across all indications while demonstrating up to 1000-fold resistance to SOCs. In summary, we found that cell line models which evade cell death upon treatment with chemo- or targeted therapies continued to present vulnerability to ferroptosis induction across both cell states. Given the heterogeneity in responses to drug-induced cell-states, understanding the mechanisms of differential drug sensitivity to GPX4 inhibition may help in formulating successful strategies for targeting this relevant cell population in the clinic, thereby limiting cancer progression and/or improving curative potential. Citation Format: Taronish Dubash, Maria Cristina Munteanu, Shrouq Farah, Cristian Nunez, Laurence Jadin, Branko Radetich, Darby Schmidt, Nadia Gurvich. Targeting drug-induced tolerant &amp; resistant cell populations by novel ferroptosis inducer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1668.
Abstract 6621: Simulating the distortion of clonal fractions in ctDNA due to spatially heterogenous selection
Authors: Thomas W. Rachman, Oana Carja, Russell Schwartz
Journal: Cancer Research (2023)

Abstract Time-series circulating tumor DNA (ctDNA) sequencing has the potential to reveal emerging variants in the tissue in real time, and there is now substantial evidence that it can detect tumor growth and treatment-resistant mutations long before growth is visible. However, the reliability of ctDNA for profiling the primary tumor may be compromised by spatial heterogeneity in the tumor genetics, for example due to selective effects of differential drug penetration, immune infiltration, and oxygenation. We explore the influence of spatial factors on tumor genetics through a lattice-based branching process model of solid tumor evolution and ctDNA shedding with the goal of understanding where spatially variable selection pressure could lead to a significant difference between the clonal fractions in the blood and the tissue. The lattice model divides space into regions with different growth rates which result in different rates of driver mutation accumulation. The effects of regional differences in selection cause different apoptosis rates to correlate with the location of expanding driver clones. Using these rates to simulate ctDNA shedding, our model found that clones fit enough to invade a hostile region are temporarily amplified in the blood compared to their tissue frequency by as much as 300% for a limited window of time before the population expands further and the clonal fraction in the blood returns to close agreement with tissue. The results suggest evolutionary contexts in which liquid biopsy might provide highly biased estimates of tumor state, but also shows how this effect might be exploited to provide more sensitive detection of clonal expansion with implications for blood-based detection of recurrence and metastasis. Citation Format: Thomas W. Rachman, Oana Carja, Russell Schwartz. Simulating the distortion of clonal fractions in ctDNA due to spatially heterogenous selection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6621.
Abstract 312: The ATR inhibitor ART0380 shows preclinical efficacy in monotherapy or in combination with gemcitabine, aPD1, PARP inhibitors and topoisomerase 1 poisons
Authors: Jayesh Bhanabhai Majithiya, Marina Roy Luzarraga, Richard Newman, Paula Costales, Philip Jones, Maria Emilia Di Francesco, Virginia Giuliani, Chris Caroll, Mary Geck Do, Tim Heffernan, Ningpeng Feng, XiaoYan Ma, Sarah lively, Michael G. Johnson, Lerin Geo, Desiree Piscitello, Eeson Rajendra, Vera Grinkevich, Marco Ranzani, Martin Stockley, Gillian Langford, Robert Heald, Helen M. Robinson, Graeme C. Smith
Journal: Cancer Research (2023)

Abstract ART0380 is a potent, selective and orally active inhibitor of ataxia telangiectasia and Rad3-related (ATR) that has been developed for treatment for cancer patients with DNA repair defects. Here we show preclinical data of ART0380 in a range of tumour xenograft models, both as monotherapy and in combination with other DNA-damaging agents. As monotherapy, ART0380 exhibits tumour PD (γH2AX) effects and efficacy comparable to the ATR inhibitor BAY-1895344 but causing less toxicity to the gut. As ATM has been highlighted as synthetic lethal with ATR, ART0380 monotherapy was also evaluated in ATM-deficient models showing strong tumour growth inhibition using both continuous and intermittent scheduling. ART0380 was also shown to have enhanced efficacy when dosed in combination with other anti-cancer agents. Here we show strong synergy when combining ART0380 with gemcitabine, the PARP inhibitor olaparib, the topoisomerase 1 poison irinotecan as well as the immuno-oncology therapeutic aPD1. Overall, these data demonstrate the high potential of ART0380 as an anti-cancer agent given as monotherapy or in combination Citation Format: Jayesh Bhanabhai Majithiya, Marina Roy Luzarraga, Richard Newman, Paula Costales, Philip Jones, Maria Emilia Di Francesco, Virginia Giuliani, Chris Caroll, Mary Geck Do, Tim Heffernan, Ningpeng Feng, XiaoYan Ma, Sarah lively, Michael G. Johnson, Lerin Geo, Desiree Piscitello, Eeson Rajendra, Vera Grinkevich, Marco Ranzani, Martin Stockley, Gillian Langford, Robert Heald, Helen M. Robinson, Graeme C. Smith. The ATR inhibitor ART0380 shows preclinical efficacy in monotherapy or in combination with gemcitabine, aPD1, PARP inhibitors and topoisomerase 1 poisons [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 312.
Abstract 3601: Tumor MK2 signaling regulates cell migration and invasion in head and neck squamous cell carcinoma
Authors: Dakota D. Okwuone, Deri Morgan, Hannah M. Smith, Grace Millington, Kiersten L. Berggren, Christopher E. Lominska, Sufi M. Thomas, Gregory N. Gan
Journal: Cancer Research (2023)

Abstract Poor 5-year overall survival in head and neck cancer (HNC) can be attributed to high rates of locoregional and distant metastasis. We have previously demonstrated that high phosphorylation/activation of MAPK-activated protein kinase 2 (MK2), a stress-activated kinase directly downstream of p38 MAPK, in head and neck squamous cell carcinoma (HNSCC) is associated with worse overall survival and inhibition of the MK2 pathway enhances in vivo HNSCC radiosensitivity. Our prior work also demonstrates that radiotherapy-induced epithelial-to-mesenchymal transition (EMT) gene expression can be suppressed in cells when MK2 is inhibited. Several studies have shown that EMT plays a prominent role in HNSCC tumor invasion, treatment resistance, and locoregional metastases to lymph nodes. In this study, we investigate the impact of MK2 activity on HNSCC tumor progression by examining its contribution to cancer cell morphology. We used lentiviral-shRNA and the CRISPR-Cas9 system to knock down/out the MK2 gene in multiple human and murine HNSCC cell lines. We measured tumor cell migration and invasion in both classic 2D in vitro culture as well as with 3D spheroids. We performed unbiased analysis via RNAseq in human HNSCC cell lines comparing MK2 shRNA vs scramble cell lines. Substantial gene and pathway alterations were examined using a combination of immunoblot and RT-qPCR. Our data shows knocking down/out MK2 in HNSCC cells significantly diminishes cell migration and invasion in 2D and 3D in vitro culture assays. RNAseq analysis demonstrated loss of MK2 leads to a significant increase in many cell adhesion molecules, including E-cadherin, and a decrease in N-cadherin, suggesting a shift from mesenchymal to more epithelial phenotype. Furthermore, we note expression of multiple matrix metalloproteinases and EMT markers (i.e., Snail) are substantially reduced in MK2 shRNA and KO cell lines. These results indicate that the MK2 pathway is involved in HNSCC motility and invasion. We also observe the loss of MK2 contributes to a shift in the epithelial:mesenchymal ratio potentially by suppressing cancer EMT plasticity. All in all, this study provides evidence suggesting tumor MK2 activation mediates HNC progression. Citation Format: Dakota D. Okwuone, Deri Morgan, Hannah M. Smith, Grace Millington, Kiersten L. Berggren, Christopher E. Lominska, Sufi M. Thomas, Gregory N. Gan. Tumor MK2 signaling regulates cell migration and invasion in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3601.
Abstract 4434: A PD-1-targeted, receptor-masked IL-2 immunocytokine with maintained potential to engage endogenous IL-2Ra drives selective stimulation of PD-1+ T cells and robust anti-tumor efficacy
Authors: Jiaxi Wu, Nicolin Bloch, Aaron Chang, Ramandeep Bhavsar, Supriya Patel, Qingqing Wang, Hassan Shakil Ahmed, Vidur Garg, Michael Amatulli, Yuetian Yan, Shunhai Wang, Drew Dudgeon, Willy Ramos, Pamela Krueger, Ashique Rafique, Tammy Huang, Erica Ullman, Aynur Hermann, William Olson, John Lin, Eric Smith, Tong Zhang
Journal: Cancer Research (2023)

Abstract Interleukin-2 (IL-2) is a key cytokine for T cell proliferation, differentiation, and effector function. Recombinant IL-2 has been used for the treatment of metastatic melanoma and renal cell carcinoma, and induced complete, durable tumor regression in some patients. ​However, its broader use in cancer immunotherapy has been limited by severe toxicity. A new generation of IL-2 therapies with decreased binding to IL-2 receptor α-chain (IL-2Rα) is being developed to reduce toxicity and Tregs expansion yet with limited clinical success so far. Here, we show that the ability to engage IL-2Rα is critical for maximal anti-tumor activity of a systemic IL-2 therapy, and an alternative approach to circumvent systemic toxicity is to deliver IL-2 specifically to tumor-reactive T cells. We developed REGN10597, a PD-1-targeted, receptor-masked IL-2 immunocytokine with attenuated systemic IL-2 activity but maintained capacity to engage endogenous IL-2Rα on PD-1+ T cells. Compared to WT IL-2, receptor masked IL-2 shows improved PK and diminished systemic toxicity in mice. REGN10597 shows PD1-targeting-dependent IL-2 activity in vitro and drives selective expansion of tumor-infiltrating PD-1+ CD8 T cells with vigorous effector functions in vivo. In preclinical syngeneic tumor models in PD-1 humanized mice, REGN10597 demonstrates robust anti-tumor efficacy both as a single agent and in combination with PD-1 or PD-L1 blocking antibodies. These findings highlight the therapeutic potential of REGN10597 as a novel targeted and receptor masked WT IL-2 therapy, supporting its clinical development for the treatment of cancer. Citation Format: Jiaxi Wu, Nicolin Bloch, Aaron Chang, Ramandeep Bhavsar, Supriya Patel, Qingqing Wang, Hassan Shakil Ahmed, Vidur Garg, Michael Amatulli, Yuetian Yan, Shunhai Wang, Drew Dudgeon, Willy Ramos, Pamela Krueger, Ashique Rafique, Tammy Huang, Erica Ullman, Aynur Hermann, William Olson, John Lin, Eric Smith, Tong Zhang. A PD-1-targeted, receptor-masked IL-2 immunocytokine with maintained potential to engage endogenous IL-2Ra drives selective stimulation of PD-1+ T cells and robust anti-tumor efficacy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4434.
Abstract 6542: Detection of androgen receptor splice variants from clinical sequencing
Authors: Suhyun Hwangbo, Sungyoung Lee, Sheehyun Kim, Hongseok Yun
Journal: Cancer Research (2023)

Abstract Androgen receptor (AR) splice variants (AR-Vs) have been widely studied on its important role in prostate cancer (PC) progression. In particular, AR-Vs lacking ligand binding domains, such as AR splice variant 7 (AR-v7) that links exon 3 and cryptic exon 3 or AR variant that losses exons 5 to 7 (ARv567es), have been demonstrated as one of the resistant mechanisms to androgen deprivation therapy in PC. Despite its clinical importance, the current algorithms to detect fusions such as TopHat-Fusion have limitation to detect intra-chromosomal rearrangements including AR-Vs. In this respect, we propose a novel approach to identify AR-Vs from targeted RNA sequencing (RNA-seq) dataset. In short, our two-step approach first gathers soft-clipped or divided reads that are adjacent to the splicing sites of AR-Vs and then yields the number of splitting reads that support the existence of AR-Vs. Next, the algorithm selects the paired-end reads whose one side and the other side are mapped to the preceding and following exons, respectively. The final number of spanning reads are calculated following to the removal of low-quality reads. We validated the proposed approach using two large-scale, independent RNA-seq datasets of PC samples: 34 samples from Seoul National University Hospital (SNUH) and 558 samples from The Cancer Genome Atlas (TCGA) dataset. Overall, our approach successfully identified samples with putative AR-Vs, including AR-v7 and ARv567es. In addition, our approach successfully detected AR-v7 with reliable number of supporting reads, from the RNA-seq dataset of AR-v7-expressing cell line. Finally, statistical analyses of 34 SNUH PC patients suggested potential detection threshold in clinical sequencing settings (at least 10 split reads and 1% proportion). In the SNUH dataset, The AR-v7 positive group, which included 6 patients (17.1%) with values above the threshold, had higher AR-v7 expression levels than the negative group (p=4.8E-04). The similar pattern was also found in the analysis of TCGA dataset. Owing to its flexibility, we also confirmed that the developed approach can be used to detection of other AR-Vs, including AR-v3 and ARv567es. We expect that the further in-depth analyses including larger samples and clinical outcomes can discover clinical applicability of AR-Vs. Citation Format: Suhyun Hwangbo, Sungyoung Lee, Sheehyun Kim, Hongseok Yun. Detection of androgen receptor splice variants from clinical sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6542.